CHANGES IN DISEASE LATENCY AND HOMEOSTASIS: 1) APP23 transgenic mice exhibit many of the patholog... more CHANGES IN DISEASE LATENCY AND HOMEOSTASIS: 1) APP23 transgenic mice exhibit many of the pathological features of Alzheimer's Disease, and the disease progression is continuous over several months. Electrophysiological measurements have shown that disease-related decreases in synaptic efficacy occur earlier in irradiated APP23 animals. 2) Using vascular polymer cast technology combined with micro-tomographic imaging, microvasculature changes following irradiation have been
The NSCOR program project is transitioning from establishing the existence of CNS responses to lo... more The NSCOR program project is transitioning from establishing the existence of CNS responses to low doses of charged particles, to an investigation of mechanisms underlying these changes and extending the irradiation paradigm to more space-like exposures. In earlier experiments we examined radiation responses of the mouse brain (hippocampus) following exposure to 250 MeV protons and 600 MeV/n iron ions. Our
Advances in the management of pediatric brain tumors have increased survival rates in children, b... more Advances in the management of pediatric brain tumors have increased survival rates in children, but their quality of life is impaired due to cognitive deficits that arise from irradiation. The pathogenesis of these deficits remains unknown, but may involve reduced neurogenesis within the hippocampus. To determine the acute radiosensitivity of the dentate subgranular zone (SGZ), 21-day-old C57BL/J6 male mice received
Summary Proceedings of the 9th International Conference on Brain Tumor Research and Therapy: 1. I... more Summary Proceedings of the 9th International Conference on Brain Tumor Research and Therapy: 1. Introduction; 2. Surgery; 3. Radiation therapy; 4. Chemotherapy; 5. Immunotherapy; 6. Growth-regulatory alterations; 7. Molecular genetics; 8. Brain tumor invasion; 9. Normal tissue damage; 10. Polyamines.
Ionizing irradiation results in significant alterations in hippocampal neurogenesis that are asso... more Ionizing irradiation results in significant alterations in hippocampal neurogenesis that are associated with cognitive impairments. Such effects are influenced, in part, by alterations in the microenvironment within which the neurogenic cells exist. One important factor that may affect neurogenesis is oxidative stress, and this study was done to determine if and how the extracellular isoform of superoxide dismutase (SOD3, EC-SOD)
During treatment of brain tumors, some head and neck tumors, and other diseases, like arterioveno... more During treatment of brain tumors, some head and neck tumors, and other diseases, like arteriovenous malformations, the normal brain is exposed to ionizing radiation. While high radiation doses can cause severe tissue destruction, lower doses can induce cognitive impairments without signs of overt tissue damage. The underlying pathogenesis of these impairments is not well understood but may involve the neural precursor cells in the dentate gyrus of the hippocampus. To assess the effects of radiation on cognitive function, 2-month-old mice received either sham treatment (controls) or localized X irradiation (10 Gy) to the hippocampus/cortex and were tested behaviorally 3 months later. Compared to controls, X-irradiated mice showed hippocampal-dependent spatial learning and memory impairments in the Barnes maze but not the Morris water maze. No nonspatial learning and memory impairments were detected. The cognitive impairments were associated with reductions in proliferating Ki-67-positive cells and Doublecortin-positive immature neurons in the subgranular zone (SGZ) of the dentate gyrus. This study shows significant cognitive impairments after a modest dose of radiation and demonstrates that the Barnes maze is particularly sensitive for the detection of radiation-induced cognitive deficits in young adult mice. The significant loss of proliferating SGZ cells and their progeny suggests a contributory role of reduced neurogenesis in the pathogenesis of radiation-induced cognitive impairments.
The hippocampus is critical for learning and memory, and injury to this structure is associated w... more The hippocampus is critical for learning and memory, and injury to this structure is associated with cognitive deficits. The response of the hippocampal microvessels after a relatively low dose of high-LET radiation remains unclear. In this study, endothelial population changes in hippocampal microvessels exposed to (56)Fe ions at doses of 0, 0.5, 2 and 4 Gy were quantified using unbiased stereological techniques. Twelve months after exposure, mice that received 0.5 Gy or 2 Gy of iron ions showed a 34% or 29% loss of endothelial cells, respectively, in the hippocampal cornu ammonis region 1 (CA1) compared to age-matched controls or mice that received 4 Gy (P < 0.05). We suggest that this "U-shaped" dose response indicates a repopulation from a sensitive subset of endothelial cells that occurred after 4 Gy that was stimulated by an initial rapid loss of endothelial cells. In contrast to the CA1, in the dentate gyrus (DG), there was no significant difference in microvessel cell and length density between irradiated groups and age-matched controls. Vascular topology differences between CA1 and DG may account for the variation in dose response. The correlation between radiation-induced alterations in the hippocampal microvessels and their functional consequences must be investigated in further studies.
Exposures to doses of radiation of 1-10 Gy, defined in this workshop as moderate-dose radiation, ... more Exposures to doses of radiation of 1-10 Gy, defined in this workshop as moderate-dose radiation, may occur during the course of radiation therapy or as the result of radiation accidents or nuclear/radiological terrorism alone or in conjunction with bioterrorism. The resulting radiation injuries would be due to a series of molecular, cellular, tissue and whole-animal processes. To address the status of research on these issues, a broad-based workshop was convened. The specific recommendations were: (1) RESEARCH: Identify the key molecular, cellular and tissue pathways that lead from the initial molecular lesions to immediate and delayed injury. The latter is a chronic progressive process for which postexposure treatment may be possible. (2) Technology: Develop high-throughput technology for studying gene, protein and other biochemical expression after radiation exposure, and cytogenetic markers of radiation exposure employing rapid and accurate techniques for analyzing multiple samples. (3) Treatment strategies: Identify additional biological targets and develop effective treatments for radiation injury. (4) Ensuring sufficient expertise: Recruit and train investigators from such fields as radiation biology, cancer biology, molecular biology, cellular biology and wound healing, and encourage collaboration on interdisciplinary research on the mechanisms and treatment of radiation injury. Communicate knowledge of the effects of radiation exposure to the general public and to investigators, policy makers and agencies involved in response to nuclear accidents/events and protection/treatment of the general public.
To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, ... more To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, appropriate models are needed that integrate the complex events that occur in the radiation-exposed organism. While the spectrum of agents in clinical use or preclinical development is limited, new research findings promise improvements in survival after whole-body irradiation and reductions in the risk of adverse effects of radiotherapy. Approaches include agents that act on the initial radiochemical events, agents that prevent or reduce progression of radiation damage, and agents that facilitate recovery from radiation injuries. While the mechanisms of action for most of the agents with known efficacy are yet to be fully determined, many seem to be operating at the tissue, organ or whole animal level as well as the cellular level. Thus research on prophylaxis/protection, mitigation and treatment of radiation injuries will require studies in whole animal models. Discovery, development and delivery of effective radiation modulators will also require collaboration among researchers in diverse fields such as radiation biology, inflammation, physiology, toxicology, immunology, tissue injury, drug development and radiation oncology. Additional investment in training more scientists in radiation biology and in the research portfolio addressing radiological and nuclear terrorism would benefit the general population in case of a radiological terrorism event or a large-scale accidental event as well as benefit patients treated with radiation.
Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. ... more Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. It may result in the loss of critical cellular components in complex systems like the central nervous system (CNS), which could lead to performance decrements that ultimately could compromise mission goals and long-term quality of life. Specific hippocampal-dependent cognitive impairment occurs after whole-body 56Fe-particle irradiation, and while the pathogenesis of this effect is not yet clear, it may involve damage to neural precursor cells in the hippocampal dentate gyrus. We irradiated mice with 1-3 Gy of 12C or 56Fe ions and 9 months later quantified proliferating cells and immature neurons in the dentate subgranular zone (SGZ). Our results showed that reductions in these cells were dependent on the dose and LET. When compared with data for mice that were studied 3 months after 56Fe-particle irradiation, our current data suggest that these changes are not only persistent but may worsen with time. Loss of precursor cells was also associated with altered neurogenesis and a robust inflammatory response. These results indicate that high-LET radiation has a significant and long-lasting effect on the neurogenic population in the hippocampus that involves cell loss and changes in the microenvironment.
CHANGES IN DISEASE LATENCY AND HOMEOSTASIS: 1) APP23 transgenic mice exhibit many of the patholog... more CHANGES IN DISEASE LATENCY AND HOMEOSTASIS: 1) APP23 transgenic mice exhibit many of the pathological features of Alzheimer's Disease, and the disease progression is continuous over several months. Electrophysiological measurements have shown that disease-related decreases in synaptic efficacy occur earlier in irradiated APP23 animals. 2) Using vascular polymer cast technology combined with micro-tomographic imaging, microvasculature changes following irradiation have been
The NSCOR program project is transitioning from establishing the existence of CNS responses to lo... more The NSCOR program project is transitioning from establishing the existence of CNS responses to low doses of charged particles, to an investigation of mechanisms underlying these changes and extending the irradiation paradigm to more space-like exposures. In earlier experiments we examined radiation responses of the mouse brain (hippocampus) following exposure to 250 MeV protons and 600 MeV/n iron ions. Our
Advances in the management of pediatric brain tumors have increased survival rates in children, b... more Advances in the management of pediatric brain tumors have increased survival rates in children, but their quality of life is impaired due to cognitive deficits that arise from irradiation. The pathogenesis of these deficits remains unknown, but may involve reduced neurogenesis within the hippocampus. To determine the acute radiosensitivity of the dentate subgranular zone (SGZ), 21-day-old C57BL/J6 male mice received
Summary Proceedings of the 9th International Conference on Brain Tumor Research and Therapy: 1. I... more Summary Proceedings of the 9th International Conference on Brain Tumor Research and Therapy: 1. Introduction; 2. Surgery; 3. Radiation therapy; 4. Chemotherapy; 5. Immunotherapy; 6. Growth-regulatory alterations; 7. Molecular genetics; 8. Brain tumor invasion; 9. Normal tissue damage; 10. Polyamines.
Ionizing irradiation results in significant alterations in hippocampal neurogenesis that are asso... more Ionizing irradiation results in significant alterations in hippocampal neurogenesis that are associated with cognitive impairments. Such effects are influenced, in part, by alterations in the microenvironment within which the neurogenic cells exist. One important factor that may affect neurogenesis is oxidative stress, and this study was done to determine if and how the extracellular isoform of superoxide dismutase (SOD3, EC-SOD)
During treatment of brain tumors, some head and neck tumors, and other diseases, like arterioveno... more During treatment of brain tumors, some head and neck tumors, and other diseases, like arteriovenous malformations, the normal brain is exposed to ionizing radiation. While high radiation doses can cause severe tissue destruction, lower doses can induce cognitive impairments without signs of overt tissue damage. The underlying pathogenesis of these impairments is not well understood but may involve the neural precursor cells in the dentate gyrus of the hippocampus. To assess the effects of radiation on cognitive function, 2-month-old mice received either sham treatment (controls) or localized X irradiation (10 Gy) to the hippocampus/cortex and were tested behaviorally 3 months later. Compared to controls, X-irradiated mice showed hippocampal-dependent spatial learning and memory impairments in the Barnes maze but not the Morris water maze. No nonspatial learning and memory impairments were detected. The cognitive impairments were associated with reductions in proliferating Ki-67-positive cells and Doublecortin-positive immature neurons in the subgranular zone (SGZ) of the dentate gyrus. This study shows significant cognitive impairments after a modest dose of radiation and demonstrates that the Barnes maze is particularly sensitive for the detection of radiation-induced cognitive deficits in young adult mice. The significant loss of proliferating SGZ cells and their progeny suggests a contributory role of reduced neurogenesis in the pathogenesis of radiation-induced cognitive impairments.
The hippocampus is critical for learning and memory, and injury to this structure is associated w... more The hippocampus is critical for learning and memory, and injury to this structure is associated with cognitive deficits. The response of the hippocampal microvessels after a relatively low dose of high-LET radiation remains unclear. In this study, endothelial population changes in hippocampal microvessels exposed to (56)Fe ions at doses of 0, 0.5, 2 and 4 Gy were quantified using unbiased stereological techniques. Twelve months after exposure, mice that received 0.5 Gy or 2 Gy of iron ions showed a 34% or 29% loss of endothelial cells, respectively, in the hippocampal cornu ammonis region 1 (CA1) compared to age-matched controls or mice that received 4 Gy (P < 0.05). We suggest that this "U-shaped" dose response indicates a repopulation from a sensitive subset of endothelial cells that occurred after 4 Gy that was stimulated by an initial rapid loss of endothelial cells. In contrast to the CA1, in the dentate gyrus (DG), there was no significant difference in microvessel cell and length density between irradiated groups and age-matched controls. Vascular topology differences between CA1 and DG may account for the variation in dose response. The correlation between radiation-induced alterations in the hippocampal microvessels and their functional consequences must be investigated in further studies.
Exposures to doses of radiation of 1-10 Gy, defined in this workshop as moderate-dose radiation, ... more Exposures to doses of radiation of 1-10 Gy, defined in this workshop as moderate-dose radiation, may occur during the course of radiation therapy or as the result of radiation accidents or nuclear/radiological terrorism alone or in conjunction with bioterrorism. The resulting radiation injuries would be due to a series of molecular, cellular, tissue and whole-animal processes. To address the status of research on these issues, a broad-based workshop was convened. The specific recommendations were: (1) RESEARCH: Identify the key molecular, cellular and tissue pathways that lead from the initial molecular lesions to immediate and delayed injury. The latter is a chronic progressive process for which postexposure treatment may be possible. (2) Technology: Develop high-throughput technology for studying gene, protein and other biochemical expression after radiation exposure, and cytogenetic markers of radiation exposure employing rapid and accurate techniques for analyzing multiple samples. (3) Treatment strategies: Identify additional biological targets and develop effective treatments for radiation injury. (4) Ensuring sufficient expertise: Recruit and train investigators from such fields as radiation biology, cancer biology, molecular biology, cellular biology and wound healing, and encourage collaboration on interdisciplinary research on the mechanisms and treatment of radiation injury. Communicate knowledge of the effects of radiation exposure to the general public and to investigators, policy makers and agencies involved in response to nuclear accidents/events and protection/treatment of the general public.
To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, ... more To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, appropriate models are needed that integrate the complex events that occur in the radiation-exposed organism. While the spectrum of agents in clinical use or preclinical development is limited, new research findings promise improvements in survival after whole-body irradiation and reductions in the risk of adverse effects of radiotherapy. Approaches include agents that act on the initial radiochemical events, agents that prevent or reduce progression of radiation damage, and agents that facilitate recovery from radiation injuries. While the mechanisms of action for most of the agents with known efficacy are yet to be fully determined, many seem to be operating at the tissue, organ or whole animal level as well as the cellular level. Thus research on prophylaxis/protection, mitigation and treatment of radiation injuries will require studies in whole animal models. Discovery, development and delivery of effective radiation modulators will also require collaboration among researchers in diverse fields such as radiation biology, inflammation, physiology, toxicology, immunology, tissue injury, drug development and radiation oncology. Additional investment in training more scientists in radiation biology and in the research portfolio addressing radiological and nuclear terrorism would benefit the general population in case of a radiological terrorism event or a large-scale accidental event as well as benefit patients treated with radiation.
Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. ... more Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. It may result in the loss of critical cellular components in complex systems like the central nervous system (CNS), which could lead to performance decrements that ultimately could compromise mission goals and long-term quality of life. Specific hippocampal-dependent cognitive impairment occurs after whole-body 56Fe-particle irradiation, and while the pathogenesis of this effect is not yet clear, it may involve damage to neural precursor cells in the hippocampal dentate gyrus. We irradiated mice with 1-3 Gy of 12C or 56Fe ions and 9 months later quantified proliferating cells and immature neurons in the dentate subgranular zone (SGZ). Our results showed that reductions in these cells were dependent on the dose and LET. When compared with data for mice that were studied 3 months after 56Fe-particle irradiation, our current data suggest that these changes are not only persistent but may worsen with time. Loss of precursor cells was also associated with altered neurogenesis and a robust inflammatory response. These results indicate that high-LET radiation has a significant and long-lasting effect on the neurogenic population in the hippocampus that involves cell loss and changes in the microenvironment.
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